Commentary on "Investigator brochures for phase I/II trials lack information on the robustness of preclinical safety studies" by Sievers et al.

Drug Delivery Technolog

Diamond films grown from fullerene precursors

Transmission Electron Microscope (TEM) techniques are applied to study the microstructure of diamond films grown from fullerene precursors. Electron diffraction and electron energy loss spectra (EELS) collected from the diamond films correspond to that of bulk diamond. Microdiffraction, high resolution images and EELS help determine that the first diamond grains that nucleate from fullerene precursors generally form on a thin amorphous carbon interlayer and seldom directly on the silicon substrate. Grain size measurements reveal nanocrystalline diamond grains. Cross section TEM images show that the nanocrystalline diamond grains are equiaxed and not columnar nor dendritic. The microstructure of small equiaxed grains throughout the film thickness is believed responsible for the very smooth surfaces of diamond films grown from fullerene precursors

Grain boundaries and grain size distributions in nanocrystalline diamond films derived from fullerene precursors

Film growth from C{sub 60}/Ar mixtures results in very pure diamond. Diamond films grown using C{sub 60} as a carbon source have been shown to be nanocrystalline with average grain sizes of 15 nm and standard deviations of 13 nm. The measured grain size distribution for two separate films, each based on measurements of over 400 grains, were found to be very similar and well approximated by a gamma distribution. Unlike typical CVD grown diamond films, these nanocrystalline films do not exhibit columnar growth. From the measured grain size distributions, it is estimated that 2% of the carbon atoms are located in the grain boundaries. The structure of the carbon in the grain boundaries is not known, but the films survive extended wear tests and hold together when the substrate is removed, indicating that the grains are strongly bound. The grain boundary carbon may give rise to additional features in the Raman spectrum and result in absorption and scattering of light in the films. We also expect that the grain boundary carbon may affect film properties, such as electrical and thermal conductivity

Diamond films grown from fullerene precursors

Fullerene precursors have been shown to result in the growth of diamond films from argon microwave plasmas. In contradistinction to most diamond films grown using conventional methane-hydrogen mixtures, the fullerene-generated films are nanocrystalline and smooth on the nanometer scale. They have recently been shown to have friction coefficients approaching the values of natural diamond. It is clearly important to understand the development of surface morphology during film growth from fullerene precursors and to elucidate the factors leading to surface roughness when hydrogen is present in the chemical vapor deposition (CVD) gas mixtures. To achieve these goals, we are measuring surface reflectivity of diamond films growing on silicon substrates over a wide range of plasma processing conditions. A model for the interpretation of the laser interferometric data has been developed, which allows one to determine film growth rate, rms surface roughness, and bulk losses due to scattering and absorption. The rms roughness values determined by reflectivity are in good agreement with atomic force microscope (AFM) measurements. A number of techniques, including high-resolution transmission electron microscopy (HRTEM) and near-edge x-ray absorption find structure (NEXAFS) measurements, have been used to characterize the films. A mechanism for diamond-film growth involving the C{sub 2} molecule as a growth species will be presented. The mechanism is based on (1) the observation that the optical emission spectra of the fullerene- containing plasmas are dominated by the Swan bands of C{sub 2} and (2) the ability of C{sub 2} to insert directly into C-H and C-C bonds with low activation barriers, as shown by recent theoretical calculations of reactions of C{sub 2} with carbon clusters

Friction and wear properties of smooth diamond films grown in fullerene-argon plasmas

In this study, we describe the growth mechanism and the ultralow friction and wear properties of smooth (20-50 nm rms) diamond films grown in a microwave plasma consisting of Ar and fullerene (the carbon source). The sliding friction coefficients of these films against Si{sub 3}N{sub 4} balls are 0.04 and 0.1 in dry N{sub 2} and air, which are comparable to that of natural diamond sliding against the same pin material, but is lower by factors of 5 to 10 than that afforded by rough diamond films grown in conventional H{sub 2}-CH{sub 4} plasmas. Furthermore, the smooth diamond films produced in this work afforded wear rates to Si{sub 3}N{sub 4} balls that were two to three orders of magnitude lower than those of H{sub 2}-CH{sub 4} grown films. Mechanistically, the ultralow friction and wear properties of the fullerene-derived diamond films correlate well with their initially smooth surface finish and their ability to polish even further during sliding. The wear tracks reach an ultrasmooth (3-6 nm rms) surface finish that results in very little abrasion and ploughing. The nanocrystalline microstructure and exceptionally pure sp{sup 3} bonding in these smooth diamond films were verified by numerous surface and structure analytical methods, including x-ray diffraction, high-resolution AF-S, EELS, NEXAFS, SEM, and TEM. An AFM instrument was used to characterize the topography of the films and rubbing surfaces

Growth of (110) Diamond using pure Dicarbon

We use a density-functional based tight-binding method to study diamond growth steps by depositing dicarbon species onto a hydrogen-free diamond (110) surface. Subsequent C_2 molecules are deposited on an initially clean surface, in the vicinity of a growing adsorbate cluster, and finally, near vacancies just before completion of a full new monolayer. The preferred growth stages arise from C_2n clusters in near ideal lattice positions forming zigzag chains running along the [-110] direction parallel to the surface. The adsorption energies are consistently exothermic by 8--10 eV per C_2, depending on the size of the cluster. The deposition barriers for these processes are in the range of 0.0--0.6 eV. For deposition sites above C_2n clusters the adsorption energies are smaller by 3 eV, but diffusion to more stable positions is feasible. We also perform simulations of the diffusion of C_2 molecules on the surface in the vicinity of existing adsorbate clusters using an augmented Lagrangian penalty method. We find migration barriers in excess of 3 eV on the clean surface, and 0.6--1.0 eV on top of graphene-like adsorbates. The barrier heights and pathways indicate that the growth from gaseous dicarbons proceeds either by direct adsorption onto clean sites or after migration on top of the existing C_2n chains.Comment: 8 Pages, 7 figure

Fit for purpose of on-the-road driving and simulated driving: a randomised crossover study using the effect of sleep deprivation

IntroductionDrivers should be aware of possible impairing effects of alcohol, medicinal substance, or fatigue on driving performance. Such effects are assessed in clinical trials, including a driving task or related psychomotor tasks. However, a choice between predicting tasks must be made. Here, we compare driving performance with on-the-road driving, simulator driving, and psychomotor tasks using the effect of sleep deprivation.Method This two-way cross over study included 24 healthy men with a minimum driving experience of 3000km per year. Psychomotor tasks, simulated driving, and on-the-road driving were assessed in the morning and the afternoon after a well-rested night and in the morning after a sleep-deprived night. Driving behaviour was examined by calculating the Standard Deviation of Lateral Position (SDLP).Results SDLP increased after sleep deprivation for simulated (10cm, 95%CI:6.7–13.3) and on-the-road driving (2.8cm, 95%CI:1.9–3.7). The psychomotor test battery detected effects of sleep deprivation in almost all tasks. Correlation between on-the-road tests and simulator SDLP after a well-rested night (0.63, p Discussion The lack of apparent correlations and difference in sensitivity of performance of the psychomotor tasks, simulated driving and, on-the-road driving indicates that the tasks may not be interchangeable and may assess different aspects of driving behaviour.Perioperative Medicine: Efficacy, Safety and Outcome (Anesthesiology/Intensive Care

Transcranial magnetic stimulation as a translational biomarker for AMPA receptor modulation

TAK-653 is a novel alpha -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-positive allosteric modulator being developed as a potential therapeutic for major depressive disorder (MDD). Currently, there are no translational biomarkers that evaluate physiological responses to the activation of glutamatergic brain circuits available. Here, we tested whether noninvasive neurostimulation, specifically single-pulse or paired-pulse motor cortex transcranial magnetic stimulation (spTMS and ppTMS, respectively), coupled with measures of evoked motor response captures the pharmacodynamic effects of TAK-653 in rats and healthy humans. In the rat study, five escalating TAK-653 doses (0.1-50mg/kg) or vehicle were administered to 31 adult male rats, while measures of cortical excitability were obtained by spTMS coupled with mechanomyography. Twenty additional rats were used to measure brain and plasma TAK-653 concentrations. The human study was conducted in 24 healthy volunteers (23 males, 1 female) to assess the impact on cortical excitability of 0.5 and 6mg TAK-653 compared with placebo, measured by spTMS and ppTMS coupled with electromyography in a double-blind crossover design. Plasma TAK-653 levels were also measured. TAK-653 increased both the mechanomyographic response to spTMS in rats and the amplitude of motor-evoked potentials in humans at doses yielding similar plasma concentrations. TAK-653 did not affect resting motor threshold or paired-pulse responses in humans. This is the first report of a translational functional biomarker for AMPA receptor potentiation and indicates that TMS may be a useful translational platform to assess the pharmacodynamic profile of glutamate receptor modulators.Stress-related psychiatric disorders across the life spa